Pleural effusion is an accumulation of fluid between the layers of tissue that line the lungs and chest cavity. Normally, the amounts of pleural fluid are too small to be detectable with routine methods (Zhou et al., Anal Bioanal Chem, 404:3123-3133 (2012); Oba et al., Respiration, 83(3):198-208 (2012)). In general, a balance between hydrostatic and oncotic pressure is forced in the visceral and parietal pleural vessels and lymphatic drainage (Burgess, Clin Chim Acta, 343(1-2):61-84 (2004)). If the balance is disturbed by disorder from all or part of the body, the rate of fluid formation exceeds that of fluid absorption, and unexpected pleural effusion occurs. Excessive amounts of such fluid can impair breathing by limiting the expansion of the lungs during inhalation which predicate the presence of pulmonary, pleural, or extrapulmonary disease (McGrath et al., Int J Clin Pract, 63(11):1653-1659 (2009)). In clinic, two different types of effusions can be developed: one is transudative pleural effusion that is caused by fluid leaking into the pleural space; the most common reasons of these effusions are heart failure, cirrhosis, and after surgery. The other is exudative effusion that usually results from leaky blood vessels, and cancer, tuberculosis, pulmonary embolism, and pneumonia account for most exudative effusions.
The first step in the evaluation of pleural effusion is to determine whether the effusion is a transudate or an exudate. For a transudative effusion, therapy should be directed toward the underlying heart failure or cirrhosis. If an effusion is exudative, effort is made to define the etiology.
Based on pathogeny, all of the effusions could be classified as malignant or benign. Malignant pleural effusions (MPEs) usually occur in the setting of cancer, particularly lung and breast cancer are a common clinical problem in patients with primary thoracic and metastatic malignancies to the thorax. The annual incidences of the MPEs are estimated to be about 150,000 to 175,000 cases in the USA and 40,000 in the UK (Uzbeck et al., Adv Ther, 27(6):334-347 (2010)). Because the prognosis and strategies of management are very different, differentiation of the MPEs, which might provide the first presenting sign of cancer, from benign pleural effusions (BPEs) is very important in the clinical therapy. Furthermore, even in the same lung cancer patient with pleural effusion, if the right information on the malignancy or benignancy of the effusion is provided, the correct staging and appropriate clinical management could be exerted.
A relatively accurate diagnosis of the cause of the effusion, transudate versus exudate, relies on Light's criteria that is a comparison of the protein and lactate dehydrogenase (LDH) in the pleural fluid to those in the blood; however, about 15 to 25% of patients with transudative pleural effusions are mistakenly identified as exudative ones; thus, additional testing is necessary. The current conventional clinical methods to diagnose MPEs include routine analysis, biochemistry test, and cytological examination. The former two have difficulty in distinguishing MPEs, and the latter is a gold standard to confirm MPEs and has high specificity; however, it is limited by low sensitivity (about 50%) (How et al., Int Med J, 4(2):30-37 (2005)). If the result of initial pleural effusion cytology is negative, at least two more pleural fluid specimens must be submitted for further examination, while some MPEs could not be diagnosed even with repeated examinations. Recently, it is popular to analyze levels of tumor markers in pleural effusions to diagnose its malignancy, such as carcinoembryonic antigen (CEA), cancer antigen (CA) 125, CA 19-9, and CA 15-3 [14-16]; however, their sensitivities are quite low, 52.8, 16.7, 52.7, and 50.0% for CEA, CA 125, CA 19-9, and CA 15-3, respectively [13], and their accuracies are still not satisfying, e.g., 85.3, 75.2, 71.5, and 40.5% for CEA, CA 15-3, CA 19-9, and CA 125, respectively (Shitrit et al., Oncologist, 10(7):501-507 (2005)).
Currently, there is no rapid and simple test for accurate diagnosis of MPE, or for informing the patients about their prognosis. There is a need for rapid and accurate diagnosis of malignant or benign pleural effusions with minimally invasive techniques. There is also a need for providing disease prognosis to subjects with malignant pleural effusion diagnosis.
Therefore, it is the object of the present invention to provide a method for rapid and accurate diagnosis of malignant disease, such as malignant pleural effusion.
It is a further object of the present invention to provide an accurate prognostic method to predict median survival time of subjects diagnosed with malignant disease, such as malignant pleural effusion.
It is a further object of the present invention to provide kits for the rapid and accurate diagnostic method for diagnosing malignant disease, such as malignant pleural effusion.